EPIC-CAD

Published

Choo MS, et al. "Edoxaban antithrombotic therapy for atrial fibrillation and stable coronary artery disease". The New England Journal of Medicine. 2024. (Epub 2024-09-01):1-13.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

Among adults with AF with elevated thromboembolic risk who also have stable CAD, does edoxaban monotherapy lower risk of AF, CAD, and bleeding events at 12 months when compared to edoxaban+antiplatelet therapy?

Bottom Line

Among adults with AF with elevated thromboembolic risk who also have stable CAD, edoxaban monotherapy is associated with lower risk of AF, CAD, and bleeding events at 12 months when compared to edoxaban+antiplatelet therapy.

Major Points

AF and stable CAD commonly coexist and the combined management proves challenging given compounded bleeding risk of each condition's targeted therapies. Specifically, guidelines recommendation the use of anticoagulation medications to lower AF-associated thromboembolic at elevated risk, and antiplatets are commonly used to lower ischemic events in CAD. The use of both anticoagulation+antiplatelet therapy for persons with AF and stable CAD (ie no recent revascularization) was called into question after publication of the 2019 AFIRE trial, which reported lower all-cause mortality when using rivaroxaban alone in comparison to rivaroxaban+antiplatelet therapy. The 2023 ACC/AHA-led AF guidelines recommend oral anticoagulation monotherapy over anticoagulation+antiplatelet therapy (COR 1, LOE B-R). Whether this benefit was observed for other DOACs was unknown.

Published in 2024, the open label Edoxaban Versus Edoxaban With antiPlatelet Agent In Patients With Atrial Fibrillation and Chronic Stable Coronary Artery Disease (EPIC-CAD) trial randomized 1,030 adults in Korea with known stable CAD and AF with elevated thromboembolic risk to edoxaban monotherapy or edoxaban+antiplatelet therapy, with the antiplatelet being selected by the treating physician. There was a significant reduction in the combined outcome (all-cause mortality, MI, stroke, systemic embolism, unplanned urgent revascularization, major bleeding, clinically relevant nonmajor bleeding at 12 months) among those in the edoxaban monotherapy group (6.8% vs. 16.2%; HR 0.44; 95% CI 0.30 to 0.65). This benefit was primarily driven by a large reduction in bleeding events. There were numerically more ischemic events in the edoxaban monotherapy group, but this did not reach statistical significance. Unlike the AFIRE trial, there was no difference in mortality.

EPIC-CAD provides additional data that persons with AF who would generally be eligible for anticoagulation therapy who also have stable CAD may benefit from the use of anticoagulation therapy alone.

Guidelines

As of September 2024, no guidelines have been published that reflect the results of this trial.

Design

• Open label RCT
• N=1,030
  • Edoxaban monotherapy (n=524)
  • Edoxaban+antiplatelet (n=516)
• Setting: 18 sites in S Korea
• Enrollment: 2019-2022
• Follow-up: 12 months
• Analysis: Intention-to-treat
• Primary outcome: All-cause mortality, MI, stroke, systemic embolism, unplanned urgent revascularization, major bleeding, clinically relevant nonmajor bleeding at 12 months

Population

Inclusion Criteria

• Aged ≥18
• Prevalent or paroxysmal AF with CHA2DS2-VASc score ≥2
• Prior CAD on medical therapy alone, deemed to be stable defined as ≥1 of the following:
  • Chronic CAD with prior PCI or CABG ≥6 months prior
  • ACS treated with PCI or CABG ≥12 months prior
  • Coronary catheterization or coronary CTA with ≥50% stenosis of major epicardial coronary artery

Exclusion Criteria

• Contraindication to antithrombotic medications (e.g., high bleed risk, prior ICH, prosthetic heart valves, mod-to-severe MS, severe liver disease, severe renal disease)
• Platelet count <50k/uL
• Life expectancy <12 months

Baseline Characteristics

From the edoxaban monotherapy group.

• Demographics: Age 72 years, male sex 76%
• Anthropometrics: Weight 68 kg, BMI 25 kg/m2
• Medical conditions: DM 43%, HTN 81%, HLD or statin use 94%, smoker 7%, HF 18%, prior cerebrovascular disease 15%, PAD 6%
• CrCl: 67 mL/min
• AF type: Paroxysmal 56%, persistent or permanent 44%
• CHA2DS2-VASc score: Mean 4.3, median 4
• HAS-BLED score: Mean 2.1, median 2
• CAD details: Obstructive CAD 36%, prior revascularization 64%
  • Prior PCI details: DES 82%, BMS 4%, both types of stents 3%, unknown stent type 12%,
  • CABG: 8%
• Prior or current PPI use: 11%
• Edoxaban dose adjustment indicated: 34%

Interventions

• Randomized to a group:
  • Edoxaban monotherapy
  • Edoxaban+antiplatelet
• The edoxaban dose was the 'standard' dose of 60 mg once per day, with dose adjustments if CrCl between 15-50 mL/min, body weight <60 kg, use of p-glycoprotein inhibitors
• Antiplatelet therapy was either aspirin or a P2Y12 inhibitor, per treating physician's discretion

Outcomes

Presented as edoxaban monotherapy vs. edoxaban+antiplatelet. The authors also present estimates of difference in outcomes in the manuscript, which are not presented here for simplicity's sake.

Primary Outcome

All-cause mortality, MI, stroke, systemic embolism, unplanned urgent revascularization, major bleeding, clinically relevant nonmajor bleeding at 12 months

6.8% vs. 16.2% (HR 0.44; 95% CI 0.30 to 0.65)

Secondary Outcomes

Mortality

All-cause: 0.6% vs. 0.7% (HR 1.29; 0.29 to 5.76)

CV: 0.4% vs. 0.2% (HR 1.66; 0.16 to 17.14)

Non-CV: 0.2% vs. 0.5% (HR 1.02; 0.14 to 7.22)

Stroke

Any: 1.4% vs. 0.8% (no HR presented as this violated the proportional hazard assumption; no statistically significant difference)

Ischemic: 1.0% vs. 0.6% (HR 1.82; 0.46 to 7.14)

Hemorrhagic: 0.4% vs. 0.2% (HR 1.64; 0.16 to 17.00)

Systemic embolism

0 vs. 0

CAD events

MI: 0 vs. 0.5% (violated proporitonal hazard assumption; no statistically significant difference)

Unplanned urgent revascularization: 1.4% vs. 1.4% (HR 1.00; 0.35 to 2.85)

Stent thrombosis: 0 vs. 0

Composite ischemic events

Major: 1.6% vs. 1.8% (HR 1.23; 0.48 to 3.10)

Major=All-cause mortality, MI, ischemic stroke, systemic embolism.

Any: 3.0% vs. 2.4% (HR 1.40; 0.67 to 2.93)

Any= all-cause mortality, MI, ischemic stroke, systemic embolism, unplanned urgent revascularization.

Subgroup Analysis

The primary event was similar by age, sex, creatinine clearance, type of prior revascularizatoin, edoxaban dose, CHA2DS2-VASc score at a threshold of 4, and HAS-BLED score at a threshold of 3.

Adverse Events

ISTH major bleeding or clinically relevant nonmajor bleeding

4.7% vs. 14.2% (HR 0.34; 0.22 to 0.53)

Fatal bleeding

0 vs. 0

Major bleeding

1.3% vs. 4.5% (0.34; 0.14 to 0.73)

Clinically relevant nonmajor bleeding

3.5% vs. 10.6% (HR 0.36; 0.21 to 0.59)

Any bleeding

9.9% vs. 20.1% (HR 0.48; 0.35 to 0.67)

ICH

0.4% vs. 0.6% (HR 0.70; 0.12 to 4.16)

GI hemorrhage

1.6% vs. 2.6% (violated proportionality assumption, no statistically significant difference)

Criticisms

• Did not exclude persons with CrCl >95 mL/min. The FDA recommends against use of edoxaban for treatment of AF in this population.
• Did not provide a subgroup analysis by the extremely clinically relevant CrCl threshold of 95.
• Open label design.
• In 1 country only.

Funding

• CardioVascular Research Foundation
• Daiichi-Sankyo
• Daewoong Pharmaceutical